Levodopa Formulations Research Articles

Novel Levodopa Formulations for Parkinson's Disease.

Levodopa remains the most effective treatment for Parkinson's disease and is considered the gold standard therapy. However, disease progression and changes in the gastrointestinal tract result in a declining window of treatment response in a majority of patients. Efforts have been made recently to improve levodopa bioavailability either by developing more effective oral formulations or by innovating routes of administration (intestinal infusion, transcutaneous or inhaled levodopa). IPX066 is a novel levodopa-carbidopa (LD/CD) oral formulation combining immediate-release (IR) and extended-release (ER) LD/CD recently approved in the USA and the EU. Levodopa-carbidopa intestinal gel (LCIG) is an approved therapy consisting of a suspension of levodopa and carbidopa infused directly into the proximal jejunum via a percutaneous endoscopic gastrojejunostomy (PEG-J) tube through a portable infusion pump. Ongoing studies are evaluating the 'accordion pill' (AP09004), an ER LD/CD formulation with gastroretentive properties. ND0612 is a proprietary liquid formulation of LD/CD that enables subcutaneous administration via a small patch-pump device, and CVT-301 is a levodopa inhalation powder with rapid onset of action; both are currently in active studies. Other novel formulations have been discontinued, including DM-1992, which is a bilayer formulation containing an IR LD/CD layer and an ER LD/CD layer with gastroretentive properties, and XP21279, a novel oral levodopa prodrug that is absorbed from the small and large intestine by high-capacity nutrient transporters expressed throughout the gastrointestinal system. ODM-101 is a new oral formulation of levodopa/carbidopa/entacapone that contains a higher amount of carbidopa (65 or 105 mg), but no active studies are underway. The current review aims to summarize the pharmacokinetic aspects, clinical efficacy, and potential adverse events of novel levodopa formulations currently available or under development.

EP 43. Impulse control disorder (ICD) and dopamine dysregulation syndrome (DDS) in Parkinson’s disease (PD) and deep brain stimulation surgery: A clinical Case

Introduction The treatment of impulse control disorder (ICD) and dopamine dysregulation syndrome (DDS) in Parkinson’s Disease (PD) is complex. It was found in some series, that PD patients undergoing bilateral subthalamic nucleus DBS surgery (stn-DBS) that previously had ICD/DDS significantly improved of that domain after surgery. This fact has prompted a growing interest in the influence that STN-DBS surgery may have in these cases. Clinical case A 52 years-old patient with juvenile PD, onset at 42 years-old, with negative genetic study (parkin/LRRK2 mutations). Six years ago started to develop motor fluctuations, initially controlled with optimization of dopaminergic replacement therapy (DRT), but two years later starts to experience complex motor fluctuations, difficult to control with DRT. Progressively his family started to note some behavioural changes, namely, pathological gambling and hypersexuality, with marked disruption of social, familiar and work life. At this point, he was on 1510 mg equivalents of levodopa (LED), and 260 mg of LED in the form of ropinirole (extended release). The dopamine agonist was gradually suspended with progressive improvement of ICD symptoms. In the last year, he started to develop DDS, reaching to 2000–3000 mg/day of LED ingested through the form of short-acting formulations of levodopa, with disabling peak dose dyskinesia, frequent falls and functional impairment. Additionally, this patient had a motor response to a levodopa challenge of 60% (MDS-UPDRS-III), cognitively presented no significant changes (MoCA: 23; DRS-II; 138), reported no depression (BDI-II: 7) or apathy (AES-C: 27), and moderate ICD (QUIP Q: sexual and DDS domains impaired) and some non-motor symptoms/fluctuations (NMSS-PD: 23; Ardouin Scale: 42). He was then submitted to bilateral stn-DBS surgery. We will present the post-surgical outcome at 8 months. Conclusion Currently, there is not enough evidence in the literature to use stn-DBS surgery as a therapy for ICD/DDS. However, in patients who otherwise meet criteria for stn-DBS this procedure can also be helpful in controlling the symptoms of ICD/DDS, which can have a major impact on social, familiar and professional life as this case demonstrates.

Prospective evaluation of pulmonary function in Parkinson's disease patients with motor fluctuations

Background. Spirometry patterns suggesting restrictive and obstructive pulmonary dysfunction have been reported in Parkinson’s disease (PD). However, the patterns’ precise relation to PD pathophysiology remains unclear. Purpose/Aim. To assess ON- versus OFF-state pulmonary function, the quality of its spirometric evaluation, and the quality of longitudinal spirometric findings in a large sample of PD patients with motor fluctuations. Methods. During a placebo-controlled trial of an inhaled levodopa formulation, CVT-301, in PD patients with ≥2 h/d of OFF time, spirometry was performed by American Thoracic Society (ATS) guidelines at screening and throughout the 4-week treatment period. Results. Among 86 patients, mean motor impairment during an OFF state at screening was moderately severe. However, mean spirometry results at screening were within normal ranges, and in a mixed model for repeated measures (MMRM), the results at screening were not dependent on motor state (ON vs. OFF). In the placebo group (n = 43), 76% of ON-state and 81% of OFF-state examinations throughout the study met ATS quality metrics, and in an MMRM analysis, mean findings at these patients’ arrivals for treatment-period visits showed no significant 4-week change. Across all 86 patients, flow-volume curves prior to any study-drug administration showed only a 3% incidence of “sawtooth” morphology. Conclusions. In PD patients with motor fluctuations, longitudinal spirometry of acceptable quality was generally obtained. Although mean findings were normal, about a quarter of spirograms did not meet ATS quality criteria. Spirogram morphology may be less indicative of various forms of respiratory dysfunction than has previously been reported in PD.

Advances in levodopa therapy for Parkinson disease: Review of RYTARY (carbidopa and levodopa) clinical efficacy and safety.

Parkinson disease (PD) is a slowly progressive, incurable, neurodegenerative disorder with progressive motor symptoms that can be managed with treatments. Levodopa is generally recognized as the most effective and widely used treatment for PD. It improves function and quality of life, morbidity, and mortality, and therefore reduces individual and societal costs. Levodopa has a relatively short half-life, however, and is quickly metabolized in the plasma, leading to fluctuations, including wearing-off of effect and inconsistent symptomatic relief as well as development of dyskinesias, with both wearing off and dyskinesias worsening with advancing disease. Immediate-release and controlled-release formulations have been used with success, but motor fluctuations remain a problem. RYTARY (levodopa and carbidopa, IPX066) is an oral extended-release therapy composed of carbidopa-levodopa microbeads designed to dissolve at various rates that allows for quick absorption and sustained levodopa release over an extended period. In development studies, RYTARY improved symptoms in patients with both early and advanced PD and offered significantly improved Unified Parkinson Disease Rating Scale scores and "on" times, without worsening troublesome dyskinesias when compared to other levodopa formulations. Tolerability and safety were comparable to other formulations. This section reviews the data that support the use of RYTARY in the treatment of PD.

Advances in levodopa therapy for Parkinson disease.

This supplement describes a recent development in the use of a drug very familiar to neurologists. The drug is levodopa, which half a century after its introduction is still widely considered the most effective oral agent for treating the motor symptoms of Parkinson disease (PD).1 The recent development is an oral formulation of levodopa plus carbidopa (RYTARY [carbidopa and levodopa] extended-release capsules), a combination of immediate- and extended-release beads with pharmacokinetic properties that produce an initial peak in levodopa plasma levels in about an hour after administration, and maintains them for 4–5 hours before declining.2

Novel Approaches to Optimization of Levodopa Therapy for Parkinson's Disease.

Levodopa (LD) is the most effective medication to treat Parkinson's disease (PD). However, motor fluctuations and drug-induced dyskinesia compromise the long-term success of levodopa therapy in PD. These response complications are due, at least in part, to fluctuating LD plasma levels (as a result of erratic gastric emptying, variable jejunal absorption, and most importantly, the short half-life of LD) with standard levodopa formulations. Keeping levodopa concentrations as constant as possible is the target for improving the pharmacokinetics and developing new ways of LD administration. In this article, we review novel oral and non-oral LD formulations including the ones that have successfully completed phase 3 clinical trials and have come to market and ones that are still in earlier phases of clinical development.

A review of current and novel levodopa formulations for the treatment of Parkinson's disease.

Parkinson's disease treatment is characterized by the nearly inevitable development of motor complications, including fluctuations and dyskinesias, in which the duration of benefit of a dose of medication is offset by involuntary movements that can be more disabling than the Parkinsonian features themselves. While levodopa remains the gold standard of therapy, it is the most likely to be associated with these complications. The concept of continuous dopaminergic stimulation has gained increasing acceptance as a potential mechanism by which to avoid or delay the development of motor complications, or to minimize their impact once they have already occurred. This article will explore existing and novel formulations of levodopa to identify their role in the spectrum of Parkinson's disease therapeutics.

Conversion to IPX066 from Standard Levodopa Formulations in Advanced Parkinson's Disease: Experience in Clinical Trials.

Background:Due to the short half-life of levodopa, immediate-release carbidopa-levodopa (IR CD-LD) produces fluctuating LD concentrations, contributing to a risk of eventual motor complications. IPX066 was designed to rapidly attain therapeutic LD concentrations and maintain them to allow a dosing interval of ∼6 hours.Objective:To extensively analyze the dosing data collected in IPX066 studies during open-label conversions from IR CD-LD alone or with entacapone (CLE) and identify patterns relevant for managing conversion in the clinical setting.Methods:Patients had ≥2.5 hours/day of “off” time despite a stable IR or CLE regimen. Suggested initial dosing conversion tables based on prior LD daily dosage were provided.Results:Of 450 patients previously treated with IR CD-LD and 110 with CLE, 87.3% and 82.7% completed conversion to IPX066, respectively. At the end of conversion, average IPX066 LD daily dosages were higher than pre-conversion dosages, with a mean conversion ratio of 2.1±0.6 for IR CD-LD and 2.8±0.8 for CLE; >90% of patients took IPX066 3 or 4 times/day, compared with a median of 5 times/day at baseline in both studies. After conversion, daily “off” time significantly decreased, with no significant increase in troublesome dyskinesia. The most common adverse event reported during conversion was nausea, with an incidence of 5.3% for conversion from IR and 7.3% from CLE.Conclusions:Among PD patients with substantial “off” time, a majority were safely converted to IPX066. The sustained LD profile from the IPX066 formulation allowed an increase in LD dose accompanied by improved motor functions, without increased troublesome dyskinesia.

A levodopa dry powder inhaler for the treatment of Parkinson’s disease patients in off periods

Adequate treatment of Parkinson’s patients in off periods with orally administered levodopa is hindered by a poor bioavailability and a slow onset of action. Hence, there is a need for a fast and reliable alternative as for instance via pulmonary administration of the drug. We developed a levodopa containing powder formulation for pulmonary delivery by a recently presented high dose dry powder inhaler (Cyclops). The objective was to produce the drug formulation by means of simple techniques such as micronization, either as pure active substance or with a minimum amount of excipients. After an initial screening on dispersion behaviour, the most promising formulation in the Cyclops was characterized in vitro over a range of pressure drops (2–6kPa) and doses (20, 30 and 40mg), representative of those to be expected in practice. A co-micronized levodopa formulation with 2% l-leucine appeared to yield the best aerosol properties for inhalation and highest delivered dose reproducibility. The combination of this particular formulation and the Cyclops inhaler seems to meet the basic requirements for satisfactory deposition in the airways. This formulation is therefore expected to be a promising candidate for the treatment of Parkinson’s patients in an off period.

New treatments for levodopa-induced motor complications.

Levodopa (l-dopa)-induced motor complications, including motor fluctuations and dyskinesia, affect almost all patients with Parkinson's disease (PD) at some point during the disease course, with relevant implications in global health status. Various dopaminergic and nondopaminergic pharmacological approaches as well as more invasive strategies including devices and functional surgery are available to manage such complications. In spite of undisputable improvements during the last decades, many patients remain significantly disabled, and a fully satisfying management of l-dopa-induced motor complications is still an important unmet need of PD therapy. This article reviews the recent trial results published from 2013 to April 2015 about pharmacological and nonpharmacological interventions to treat motor complications. Randomized controlled trials conducted in patients suffering from already established complications showed that new levodopa (l-dopa) formulations such as intrajejunal l-dopa-carbidopa infusion and bilayered extended-release l-dopa-carbidopa (IPX066) can improve motor fluctuations. Positive results were also obtained with a new monoamine oxidase B (MAO-B) inhibitor (safinamide) and a catechol-O-methyltransferase COMT inhibitor (opicapone). Pilot data suggest that new formulations of dopamine agonists (inhaled apomorphine) are also of potential interest. The development of novel nondopaminergic adenosine A2A antagonists (istradefylline, preladenant, and tozadenant) to treat motor fluctuations showed conflicting results in phase 2 and phase 3 trials. For dyskinesia, trials with new amantadine extended-release formulations confirmed the interest of the glutamatergic N-methyl-d-aspartate (NMDA) antagonist approach. Positive pilot antidyskinetic effects were also recently reported using serotonin agents such as eltoprazine and glutamate mGluR5 modulators such as mavoglurant. However, the translation to clinical practice of such innovative concepts remains challenging, because subsequent phase 2 trials conducted to confirm the antidyskynetic effects of mavoglurant failed, leading to the interruption of the development of this compound for this indication.

Comparison of the pharmacokinetics of an oral extended-release capsule formulation of carbidopa-levodopa (IPX066) with immediate-release carbidopa-levodopa (Sinemet(®)), sustained-release carbidopa-levodopa (Sinemet(®) CR), and carbidopa-levodopa-entacapone (Stalevo(®)).

IPX066 (extended‐release carbidopa‐levodopa [ER CD‐LD]) is an oral extended‐release capsule formulation of carbidopa and levodopa. The single‐dose pharmacokinetics of ER CD‐LD (as 2 capsules; total dose, 97.5 mg‐390 mg CD‐LD) versus immediate‐release (IR) CD‐LD (25 mg‐100 mg), sustained‐release (CR) CD‐LD (25 mg‐100 mg), and CD‐LD‐entacapone (25 mg‐100 mg‐200 mg) was evaluated in healthy subjects. Following IR dosing, LD reached peak concentrations (Cmax) at 1 hour; LD concentrations then decreased rapidly and were less than 10% of peak by 5 hours. With CR CD‐LD and CD‐LD‐entacapone, LD Cmax occurred at 1.5 hours, and concentrations were less than 10% of peak by 6.3 and 7.5 hours, respectively. The initial increase in LD concentration was similar between ER CD‐LD and IR CD‐LD and faster than for CR CD‐LD and CD‐LD‐entacapone. LD concentrations from ER CD­­‐LD were sustained for approximately 5 hours and did not decrease to 10% of peak until 10.1 hours. Dose‐normalized LD Cmax values for ER CD‐LD were significantly lower (P< .05) than for the other CD‐LD products. Bioavailability of LD from ER CD‐LD was 83.5%, 78.3%, and 58.8% relative to IR CD‐LD, CR CD‐LD, and CD‐LD‐entacapone, respectively.

Catechol-O-methyltransferase inhibitors in Parkinson's disease.

Inhibitors of catechol-O-methyltransferase (COMT) are commonly used as an adjunct to levodopa in patients with Parkinson's disease (PD) for the amelioration of wearing-off symptoms. This narrative review aims to discuss the role of COMT inhibitors on peripheral levodopa metabolism and continuous brain delivery of levodopa, and to describe their metabolic properties. Oral application of levodopa formulations with a dopa decarboxylase inhibitor (DDI) results in fluctuating levodopa plasma concentrations, predominantly due to the short half-life of levodopa and its slowing of gastric emptying. Following transport across the blood-brain barrier and its metabolic conversion to dopamine, these peripheral 'ups and downs' of levodopa are reflected in fluctuating dopamine levels in the synaptic cleft between presynaptic and postsynaptic dopaminergic neurons of the nigrostriatal system. As a result, pulsatile postsynaptic dopaminergic stimulation takes place and results in the occurrence of motor complications, such as wearing-off and dyskinesia. More continuous plasma behaviour was observed after the combination of levodopa/DDI formulations with COMT inhibitors. These compounds also weaken a levodopa/DDI-related homocysteine increase, as biomarker for an impaired methylation capacity, which is involved in an elevated oxidative stress exposure. These findings favour the concept of chronic levodopa/DDI application with concomitant inhibition of COMT and monoamine oxidase, since deamination of dopamine via this enzyme also generates free radicals. This triple combination is suggested as standard levodopa application in patients with PD who need levodopa, if they will tolerate it.

Current treatment and future prospects of dopa-induced dyskinesias.

Levodopa-induced dyskinesias (LID) are one of the main issues in the management of Parkinson's disease (PD); once these dyskinesias are established treatment becomes difficult, so preventive strategies should be first evaluated. Although levodopa (LD) treatment has recently been related as risk factor for LID, the main strategy to delay LID is to start PD treatment with dopamine agonists, adding LD at low doses. After LID onset, approaches include reducing single LD doses, reducing or discontinuing monoamine oxidase type B/catechol O-methyltransferase (MAO-B/COMT) inhibitors and extended-release (ER) LD. Amantadine represents the best antidyskinetic tool, and ER amantadine is the most promising upcoming antidyskinetic drug. New LD formulations such as IPX-066 (able to provide continuous dopaminergic stimulation) also represent promising new approaches. The involvement of a nondopaminergic system in the pathogenesis of LID suggests that the modulation of glutamate, serotonin and adenosine could have potential as new upcoming drug targets, but the role of such drugs will still need to be confirmed in randomized controlled trials.

Continuous Drug Delivery in Parkinson’s Disease

Development of motor and non-motor complications during the course of Parkinson's disease (PD) is a major challenge for therapeutic management. At advanced disease stages, patients frequently fluctuate between PD symptoms-such as bradykinesia-and dyskinesias, in response to fluctuations in drug concentrations. Continuous subcutaneous infusion of the dopamine agonist apomorphine or intestinal infusion of levodopa reduce such fluctuations in both pharmacokinetics and motor function. This is the basis for the concept of continuous drug delivery in PD, and the more theoretical concept of continuous dopaminergic stimulation. These expressions are sometimes used to describe a treatment that is more continuous in its pharmacokinetic profile or that produces more sustained effects, compared with immediate-release levodopa, i.e. not only pump treatments. For example, sustained-release formulations of levodopa or dopamine agonists, transdermal delivery of rotigotine, and addition of catechol-O-methyltransferase inhibitors or monoamine oxidase-B inhibitors have been developed with the aim to provide more continuous drug concentrations, sustained benefits and minimized side effects. Progress has been made, but there are still knowledge gaps regarding how these treatment alternatives can be optimally used. New treatments are currently being developed to provide the continuous drug delivery that is known to successfully alleviate motor and non-motor complications. Hopefully, although not yet proven, these new methods may also prevent or postpone some of the late-stage complications.

Role of magnetic resonance spectroscopy in differentiating parkinsonian syndromes of various etiologies

Role of magnetic resonance spectroscopy in differentiating parkinsonian syndromes of various etiologies

Continuous dopaminergic delivery to minimize motor complications in Parkinson’s disease

Motor fluctuations and dyskinesias are common sequelae of Parkinson’s disease (PD) that may limit function and quality of life. With disease progression, striatal dopamine concentration becomes closely linked to plasma levodopa levels, which vary considerably with standard oral regimens. Exposure of striatal dopamine receptors to wildly fluctuating transmitter levels is thought to contribute to the development of dyskinesias and motor fluctuations. Continuous dopaminergic delivery has been shown to reduce motor complications in advanced PD patients, and has been hypothesized to prevent their incidence when given as early therapy in mild PD. In this article, the authors outline the rationale for continuous dopaminergic delivery and review clinical strategies implementing the concept, including transdermal rotigotine, subcutaneous apomorphine infusion, intraduodenal infusion of levodopa gel and the investigational oral levodopa formulation IPX066.

Initial Treatment of Parkinson’s Disease: An Update

This is an update to an article published in this journal in 2006, which covered the initial treatment of Parkinson's disease (PD). In this update, we review new research into symptomatic treatments, potential disease modifying ("neuroprotective") agents, and evidence-based reviews of current treatment. We discuss the usage of the MAO-B inhibitors, including the controversy surrounding the possible neuroprotective effects of rasagiline. Usage of extended release formulations of pramipexole and ropinirole, as well as the transdermal dopamine agonist rotigotine, are reviewed. Side effects of the dopamine agonists are discussed, including the cardiac side effects of ergot-derived dopamine agonists, and the impulse control disorders associated with the dopamine agonists. The use of zonisamide as an agent for PD tremor is reviewed. We touch on the clinical research into the benefits of exercise in PD, and briefly review some of the current studies for new formulations of levodopa and other medications and treatments with novel mechanisms of action.

Pharmacokinetic Considerations for the Use of Levodopa in the Treatment of Parkinson Disease

Parkinson disease (PD) is a progressive, disabling, neurodegenerative disorder characterized by both motor and nonmotor symptoms. Monoamine oxidase B inhibitors, dopamine agonists, N-methyl-D-aspartate antagonists and levodopa (LD), with its various formulations and administration modes, mainly improve the motor symptoms in PD, which are thought to be related to decreased dopamine levels in the brain. Of these therapeutic drug options, LD represents the most effective and best tolerated compound when it is administered several times a day. Pharmacokinetic trials of oral LD/dopa decarboxylase inhibitor (DDCI) formulations with and without the catechol-O-methyltransferase inhibitor, entacapone, showed that repeated administration with entacapone causes an increase in both the maximum concentration (Cmax) and time to Cmax (Tmax) of LD. In addition, gastrointestinal motility may also impact plasma LD behavior. These peripheral components of LD metabolism contribute to the onset of motor complications, which are predominantly associated with LD/DDCI owing to its short plasma half-life. The increase in Tmax is related to a slower increase in plasma LD concentrations after repeated LD/DDCI intake, which may also increase the risk of wearing off. An elevation in Cmax after reiterated LD intake increases the risk of peak-dose dyskinesia. Therefore, it may be useful to start with higher doses of LD formulations in the morning and then to titrate with different LD doses during the day according to the individual patient's motor behavior, which is particularly characterized by the onset of motor complications, such as off periods and dyskinesia, in more advanced stages of PD.

Emerging therapies for Parkinsonʼs disease

The experimental therapeutics of Parkinson's disease are reviewed, highlighting the current pipeline of emerging therapeutic approaches. This review includes novel approaches to dopaminergic drug delivery such as intraintestinal infusions or new extended-release formulations of levodopa and also intrapulmonary delivery of apomorphine as well as novel dopaminergic agents like the monoamine oxidase-B inhibitor safinamide or novel catechol-O-methyl transferase inhibitors. An even greater number of ongoing clinical trials assess the efficacy and safety of nondopaminergic approaches to enhance motor control or reduce motor complications like fluctuations and dyskinesias. These include adenosine A2A antagonists, α-adrenergic and serotonergic agonists as well as drugs acting on the glutamatergic system. Gene-based or cell-based intrastriatal delivery of therapeutic principles that enhance striatal dopaminergic transmission directly or via the stimulation of trophic activity has also reached phase II clinical development with encouraging results in some studies. Finally, a wide spectrum of agents with a potential for slowing disease progression is currently tested. A variety of medical and nonmedical interventions in different phases of clinical development provide an interesting and promising portfolio of emerging therapies for Parkinson's disease.

Off spells and dyskinesias: Pharmacologic management of motor complications

There are two major causes of disability in patients with Parkinson disease: motor fluctuations that occur when a dose of levodopa becomes ineffective, leading to a "wearing off," and hyperkinetic movements (dyskinesias) caused by excessive levels of dopamine. The utility of continuous levodopa treatment is therefore limited by motor complications. Pharmacologic options to treat wearing off include adding (or increasing the dosage of) levodopa, adding (or increasing the dosage of) a dopamine agonist, or adjunctive treatment with a monoamine oxidase inhibitor or catechol-O-methyltransferase inhibitor. Dyskinesias will respond to a reduction in levodopa dosage at the expense of worsening parkinsonism and an increase in the number of "off" episodes. Continuous dopamine stimulation may overcome the pulsatile stimulation of postsynaptic dopamine receptors produced by standard oral formulations of levodopa that lead to motor complications.